It is well known in the medical arts that the use of medical devices such as catheters and the like which penetrate and remain in contact with living tissues is problematic because of infections caused by microbial growth which occurs at the interfaces of these devices with the tissues over extended periods of time.
The antibacterial activity of heavy metal ions such as gold, silver or copper is well known. These heavy metal ions are often referred to as being "oligodynamic" (for instance, this term is utilized to describe the anti-microbial activity of heavy metal ions in The Journal of Urology, Vol. 121, January 1979, page 40). Oligodynamic agents are especially noted for their ability to provide an antibacterial effect in small quantities. These agents are utilized in medical technology for equipping plastic endoprostheses or hose-shaped catheters and the like, such as urine tube catheters, in order to provide the same with antimicrobial activity for extended periods of time.
For instance, U.S. Pat. No. 4,054,139 (Crossley) discloses the application of at least one oligodynamic agent on both the exterior and interior surfaces of tube-like catheters. By "exterior surface" it is meant that surface which comes in contact with body tissues, while "interior surface" denotes that portion of the device through which fluids may flow in or out of the body. The oligodynamic agent is present in thin layers of about 0.001 inch thickness or less of a solid coating formed by 10% by weight micron-sized particles of the agent in an essentially immobile, highly viscous suspension of human albumin. The coating may be placed on a proteinaceous matrix or a matrix formed from organic plastics such as polyethylene, polyvinyl-chloride, and polytetrafluoroethylene.
U.S. Pat. No. 4,612,337 (Fox, Jr. et al.) discloses a method for making the surface of such a medical device more absorbent for oligodynamic agents by soaking the polymeric material of the device with a solution of an oligodynamic agent dissolved in an organic solvent such as ethanol, soaking the polymeric material with an organic solvent for a metal salt, and thereafter resoaking the polymeric material in the solution of oligodynamic agent in organic solvent. The polymeric material is dried after each soaking step, the last time after washing. Suitable polymeric materials were said to include polyamide, polyester, polyethylene, polypropylene, polystyrene, polytetrafluoroethylene, polyurethane, polyvinylchloride, cellulose acetate, silicone elastomers, collagen, and silk. The intermediate soaking step is said to appreciably increase the incorporation of the oligodynamic agent into the polymeric material.
While the increased incorporation of the oligodynamic agent has been found to be advantageous, the process according to the afore-mentioned Fox, Jr. et al. patent is unsatisfactory because it is time, labor and cost intensive, especially when it is desired to equip the medical device with antimicrobial action on both the interior and exterior surfaces.
Furthermore, since the oligodynamic agents which are present are only bound in the surface zones of the polymer material, their availability is limited as to time and due to their brief residence on the surface. During long-term treatment this translates into a frequent, painful and risky exchange with newly coated devices.
Another problem arises when the devices to be used intracorporally have a spatial form which is not "two-dimensional", i.e., catheters and prostheses. The ability to embed such devices with oligodynamic agents is limited by slightly larger material thicknesses. In the case of silicone elastomers, the ability to embed oligodynamic agents to any appreciable depth from the surface is limited because the inner areas of this material are not sufficiently accessible to body fluids to promote the release of metal ions (due to the hydrophobic properties of the silicone elastomer itself). Therefore, even if these substances are embedded more deeply into the silicone elastomer, there is no available carrier means by which they can migrate to the surface in order to display their antimicrobial activity in the body tissue surrounding the catheter.
Alternatively, the use of materials which are sufficiently hydrophilic (such as polyurethane) to allow the exposure of deeply embedded oligodynamic to body fluids would appear to allow the reversible embedment of these substances down to their innermost zones. However, it has been found that devices with such a design have, as measurements have shown, such low delivery rates for oligodynamically active substances that a sufficient quantity of active metal ions, as measured by the concentration of the germs to be destroyed, is not available for long-term application.
Finally, European Pat. No. 0 068 385, discloses the pronounced antithrombogenic action of an elastomer comprising a polyurethane or a polyurethane urea containing an organic silicon polymer in the main chain and the advantageous use of the same for medical formed parts which are brought into direct contact with blood. Therein, block copolymers known from U.S. Pat. No. 3,562,352 (Nyilas) of a polyurethane and an organic silicone polymer with less silicone than polyurethane units are discussed with respect to their mechanical and antithrombogenic properties upon direct contact with blood and a novel advantageous variant is described wherein 1 to 50%, and preferably 4 to 15% by weight of an organic silicone polymer with a molecular weight of 500 to 10,000 and softening polyether or polyester segments are introduced into the polymer main chain. However, European Pat. No. 0 068 385 is limited to its discussion of the antithrombogenic activity of the elastomer. There is no suggestion therein to coat or embed any type of medicinally active agents, and more specifically antimicrobial agents, onto the surface of this elastomer or otherwise.
It is an object of the present invention to provide a medical device which can be used on or in the living body and can penetrate body tissues which exhibits a substantially increased delivery capacity for antimicrobial (oligodynamic) agents which give off metal ions and which has good tissue compatibility.
It is another object o the present invention to provide a medical device which is capable of releasing oligodynamic agents in controlled amounts over an extended period of time to both its interior and exterior surfaces when it comes into contact with body fluid, etc.
It is a further object of the present invention to provide a method for manufacturing a medical device in which a spatially uniform embedment of the oligodynamic agent into the polymeric matrix is made possible without the necessity of elaborate mechanical or chemical after-treatment of the material or the finished part.